The present invention relates to novel compounds, pharmaceutical compositions, and methods of use for the treatment of diseases in which products of lipoxygenase enzyme activity or the action of leukotrienes contribute to the pathological condition. Selected novel intermediates are also the present invention. The novel 2-hydroxybenzamides and N-substituted-2-hydroxy-.alpha.-oxo-benzeneacetamides of the present invention are lipoxygenase inhibitors providing activity useful for treating asthma, allergies, cardiovascular diseases, migraines, and immunoinflammatory conditions.
More particularly, this invention concerns certain novel 2-hydroxybenzamides and novel 2-hydroxy-.alpha.-oxo-benzeneacetamides having the Formula I as defined below, pharmaceutical compositions having the novel 2-hydroxybenzamides and novel 2-hydroxy-.alpha.-oxobenzeneacetamides therein, and methods of use therefore in the treatment or amelioration of diseases in which products of lipoxygenase enzyme activity or the reaction of leukotrienes contribute to the pathological condition. Lipoxygenase enzymes are part of the arachidonic acid cascade.
Arachidonic acid serves as the biological precursor for a family of physiologically active eicosanoids. These include products derived from the action of cyclooxygenase such as the class of prostaglandin-E and -F compounds, thromboxanes, and prostacyclin, and products derived from the action of lipoxygenase enzymes such as hydroxy- and hydroperoxyeicosatetraenoic acids and the leukotrienes.
Lipoxygenase pathway products such as the leukotrienes B4, C4, D4, and E4, 5-hydroxyeicosatetraenoic acid, 5-hydroperoxyeicosatetraenoic acid, and 12-hydroxyeicosatetraenoic acid are involved in the condition recognized as inflammation, and in allergic and immune responses.
These lipoxygenase products have been shown to be highly potent stereospecific inducers of polymorphonuclear leukocyte migration or chemotaxis, lysosomal enzyme release, and degranulation. Additionally, these products induce the contraction of smooth muscle such as vascular and pulmonary tissue, and induce the generation of additional inflammogens such as thromboxane A2 and prostacyclin. Lipoxygenase products also interact with vasodilator prostanoids and other mediators, leading to the enhancement or amplification of the inflammatory response.
Leukotrienes and the hydroxy- and hydroperoxyeicosatetraenoic acids play a major role in the pathogenesis of many disease conditions. These compounds have been found in synovial fluid of rheumatoid joints, in involved skin of psoriatic patients, in inflammed colonic tissue, and at elevated levels in ischemic myocardial tissue. They are also mediators of allergic and asthmatic conditions.
Compounds and pharmaceutical compositions in accordance with the present invention inhibit lipoxygenase or the biosynthesis or biochemical action of leukotrienes and, therefore, are useful in the treatment or amelioration of a number of diseases whose pathogenesis involves the production of the leukotrienes and other lipoxygenase-derived products. These lipoxygenase inhibitors aid in the prevention of tissue damage and inflammation which result from infiltration of leukocytes, release of tissue-digesting lysosomal enzymes, and changes in the permeability and contractile state of smooth muscle tissue.
Specific conditions in which such lipoxygenase-inhibiting compounds and pharmaceutical compositions in accordance with the present invention are useful include allergy; asthma; arthritis; skin disorders including psoriasis and acne; inflammation; inflammatory bowel diseases; pain; and cardiovascular disorders including myocardial ischemia and infarction, angina, arrhythmias, stroke, and atherosclerosis.
"Derivatives of 3-, 4-, and 5-phenylsalicylamides" by H. Jules, et al, J. Am. Pharm. Assoc., Sci. Ed. 45, 277-81 (1956) as reviewed in CA50:16715 describes selected phenylsalicylamides having a phenyl substituent on the phenyl moiety of the phenylsalicylamides and thus differing from the present invention.
Also falling within the scope of the present invention are the pharmaceutically acceptable acid and base addition salts of the compounds of the present invention.